Download Lactose Free, Direct Compression Formulation Used to Produce

Technical Data
Direct Compression
Loratadine Formulation
Lactose Free, Direct Compression Formulation Used to Produce Loratadine
(10 mg) Tablets
INTRODUCTION
Loratadine is a popular over-the-counter, nonsedating antihistamine used for the temporary relief
of symptoms caused by hay fever or other upper
respiratory allergies. Loratadine works by blocking
the action of histamine, a natural substance in the
body that is released by the immune system during
an allergic reaction. Many marketed loratadine
products use lactose as the main filler ingredient.
Lactose, one of the most commonly used fillers in
solid dosage formulations, is well known for
producing tablets with high mechanical strength.
However, its usage has been eroded by some
relatively recent concerns, such as Bovine
Spongiform
Encephalopathy
BSE,
Variant
Creutzfeldt-Jacob Disease (vCJD), and lactose
intolerance. These concerns have led some
formulators to evaluate other excipients in their
formulations. In addition, the abrasiveness of
lactose can cause a decrease in tooling life due to
excess wear on tableting or capsule-filling
equipment. To overcome abrasiveness, lubricants
must be used, but high lubricant levels can cause a
decrease in tablet mechanical strength and can
affect disintegration and dissolution.
OBJECTIVE
This study was conducted to determine the possible
benefits of using Starch 1500® in a loratadine
Table 1.
product. The objective of the study was to produce
a direct compression loratadine formulation without
the use of lactose while providing acceptable tablet
properties. This study also evaluated two different
lubricants to determine their effect on tablet
properties in this non-lactose system.
Starch 1500® is a multi-functional excipient
designed specifically for use in the formulation of
pharmaceutical oral solid dosage forms. Starch
1500® brings benefits to formulations through
binding
capability,
improved
disintegrant
properties, and enhanced flow and lubricity.
Manufactured exclusively for the global
pharmaceutical market, Starch 1500® is a
pharmaceutical grade of partially pregelatinized
maize starch.
MATERIALS AND METHODS
A base formulation of half microcrystalline
cellulose (MCC) and half Starch 1500® was chosen
for this drug. Table 1 lists the ingredients used and
their levels. MCC has excellent compressibility but
has limited disintegration properties. The inclusion
of Starch 1500® adds bulk to the tablet and provides
disintegration functionality. Two formulations
using different lubricants were manufactured.
For each formulation prepared, a multi-step
blending process was used in order to ensure proper
distribution of the active. Initially, half of the
Formulations
Ingredients[Manufacturer]
Formula 1
Formula 2
Percent
mg / tablet
Percent
mg / tablet
Loratadine USP [Tricon Enterprises]
6.67%
10.00
6.67%
10.00
Pregelatinized Starch NF [Starch 1500®, Colorcon]
46.42%
69.63
46.29%
69.44
Microcrystalline Cellulose NF [Emcocel® 90M, JRS Pharma]
Colloidal Silicon Dioxide NF [Cab-o-sil® M-5P, Cabot]
46.42%
69.63
46.29%
69.43
0.25%
0.37
0.25%
0.38
Magnesium Stearate NF [Mallinckrodt]
0.25%
0.37
--
--
--
--
0.50%
0.75
100.00%
150.00
100.00%
150.00
Stearic Acid NF [Oleotec]
Total
Starch 1500® was combined with the drug and
colloidal silicon dioxide. This mixture was blended
in a twin shell “V” blender for 5 minutes. The
mixture was then discharged and passed through a
40-mesh screen by hand. This step not only breaks
up the silicon dioxide but also helps to distribute
the active. The screened mixture was returned to
the blender and the remainder of the Starch 1500®
was added and blended for an additional 5 minutes.
The MCC was then added and blended for 10
minutes. The magnesium stearate was added last
and blended for 5 minutes. In Formula 2, stearic
acid was added with the MCC because, unlike
magnesium stearate, it is not sensitive to blending
time. Both magnesium stearate and stearic acid
were passed through a 60-mesh screen prior to
weighing.
Table 2.
Moisture content by loss on drying (LOD) was
determined using a Denver Instruments IR-20
moisture balance at a temperature of 105°C.
Particle size analysis was performed with an ATM
Sonic Sifter under the following conditions: sample
size 10 g ± 0.1 g, test time 5 minutes, amplitude 4,
sift-pulse setting. Bulk and tapped density were
performed in accordance with USP method 1. The
geometric mean particle sizes and standard
deviations were determined by plotting the weight
percent greater than a given diameter (on a
probability scale) versus the log of the diameter and
performing a linear regression. Tablets were
compressed using an instrumented (SMI) Piccola
(Riva) 10-station, rotary tablet press at 20 RPM.
Compression force varied from 3 to 24 kN. Tablet
properties, hardness, thickness, and weight were
measured on an Erweka Multicheck. Friability was
performed at 100 drops and disintegration times
were measured in DI water. Dissolution was tested
in accordance with USP 28 in 0.1N HCl.
The lubrication properties of magnesium stearate
and stearic acid are quite different and can affect
the compressibility of plastically deforming
materials such as pregelatinized starch and MCC.
Magnesium stearate coats the surfaces of the
granules. This coating effect builds the longer it is
blended. For materials that fracture upon
compression, new uncoated surfaces are exposed
and bonding is not adversely affected.
Blend Properties – Formula 2
Loss On Drying
6.8%
Bulk Density
Tapped Density
0.50 g/cc
0.71 g/cc
Geometric Mean Particle Size
Geometric Standard Deviation
73 microns
1.8
Formula 2, the silicon dioxide also acts as an antiadherent. Stearic acid does not have good antiadherent properties and can, on occasion, result in
punch filming or lower punch binding. When
colloidal silicon dioxide is used, typically at half
the level of the stearic acid, these concerns can be
eliminated. The average tablet weight variation for
Formula 2 was 0.81%.
Stearic acid particles remain as discrete particles in
the blend. When the blend is compressed, the
lubricant melts and extrudes to the die walls and
punch surfaces. It is important to evaluate the levels
of lubricant in each formulation and determine its
effect on compressibility and ejection force.
Magnesium stearate is a more effective lubricant
than stearic acid. Typically, stearic acid must be
used at higher levels in order to achieve similar
ejection forces. In this study, stearic acid was used
at 0.5% and magnesium stearate was used at 0.25%.
The ejection forces measured for Formula 1,
containing magnesium stearate, were approximately
half of those of Formula 2, containing stearic acid.
While higher, the ejection forces of the stearic acid
formula were well within the acceptable range (see
Figure 1, next page). Both formulations utilized
Starch 1500®, which exhibits self-lubricating
properties; therefore, high lubricant levels are not
typically required. The choice of lubricant would
depend on the formulator’s or the company’s
preference and the targets set for the resulting
tablets.
RESULTS AND DISCUSSION
Both formulations performed well, producing low
weight variation, high tablet hardness and low
friability. Low friability is an important tablet
property, especially for film-coated products.
Properties of the final blends were similar and the
data for Formula 2 is listed in Table 2. Formula 1
contains silicon dioxide to enhance the flow of the
blend. Direct compression formulations require
good flow in order to maintain proper weight
uniformity. For the compression study, the average
tablet weight variation (%RSD) was 0.75%. In
Because of the method of action of the lubricants,
differences in tablet hardness were observed. Table
2
Disintegration times for both formulations were
rapid. Formula 2, containing stearic acid, which
also had higher hardness, disintegrated faster than
Formula 1, containing magnesium stearate. This
may be due to the hydrophobicity of magnesium
stearate. Figure 3 shows the dissolution profile of
Formula 1 compared to the marketed Claritin®
lactose-based formulation. Starch 1500® not only
provided binding action that produced good
mechanical strength in these formulas, but it also
acted as a disintegrant, causing a rapid breakdown
of the tablet and fast release of the drug.
3 lists the tablet properties when a compression
force of 15 kN was used to compress each formula.
Figure 1. Ejection Force Profile
Ejection Force (N)
500
450
Formula 1 - MgSt
400
Formula 2 - StA
350
300
250
200
150
100
Figure 3. Dissolution Comparison – Media 0.1N HCl
50
0
2
4
6
8
10 12 14 16
Compression Force (kN)
18
20
100
22
Percent Released
80
Table 3. Tablet Properties
Weight
Formula 1
Formula 2
148 mg
147 mg
Hardness
7.0 kp
8.6 kp
Friability
0.05%
0.07%
Thickness
3.65 mm
3.59 mm
Disintegration Time
2.8 min
1.2 min
55 N
111 N
Ejection Force
60
40
20
Starch 1500® Formula
Claritin® Formula
0
0
Tooling: Round 9/32” standard concave
Compression Force: 15 kN
10
20
30
40
Time (min)
50
60
Table 4 compares the disintegration times of the
products and the amount of drug released in 10
minutes. The disintegration time of the Claritin®
formula was acceptable; however, the Starch
1500®-formula resulted in the much higher
dissolution rate of the tablets. At the 10-minute
time point, the Starch 1500® formulation released
99% of the drug while the lactose formulation
released only 41%. Table 5 lists the ingredients
contained in the Claritin® product.
Both formulations produced very similar
hardnesses throughout the compression force range.
Both formulations also showed a maximum
hardness at approximately 18 kN of compression
force. Figure 2 shows the compression profiles for
both formulas and clearly shows improved hardness
with the use of stearic acid. Both formulations
produced very low friability values.
Table 4. Comparison of Products
Figure 2. Compression Profile
Disintegration
Time
10
9
Hardness (kp)
8
Starch 1500® Tablets
2.8 min
Claritin® Tablets
5.1 min
Dissolution
99% released in
10 minutes
41% released in
10 minutes
7
6
Table 5. Claritin® Qualitative Formula
5
Loratadine
4
Formula 1 - MgSt
3
Lactose
Formula 2 - StA
Corn Starch
2
2
4
6
8
10
12
14
16
Compression Force (kN)
18
20
22
Magnesium Sterate
3
CONCLUSIONS
These formulations containing Starch 1500®
produced tablets with excellent hardness and
friability values without the use of lactose as a
diluent. Higher tablet hardness was attained with
the formulation containing stearic acid as the
lubricant. Both formulations exhibited low ejection
forces while using low levels of lubricants, thereby
reducing stress and wear on tooling and machinery.
The use of Starch 1500® was also responsible for
the rapid disintegration of the tablets. For tablets
produced at 15 kN of compression force, Formula 2
disintegrated in half the time of Formula 1 even
though the hardness of Formula 2 was higher. The
dissolution of loratadine from the Starch 1500®based tablets was rapid compared to the
commercial lactose-based Claritin® formulation.
These results show the strong disintegration
functionality of Starch 1500®. In addition to these
benefits, a formulation containing Starch 1500® and
microcrystalline cellulose rather than lactose would
show improved physical stability, as described in
Colorcon Technical Data Sheet – Lactose
Replacement with Starch 1500® in a Direct
Compression Formulation.
4
World Headquarters
Colorcon
415 Moyer Blvd., P.O. Box 24, West Point, PA 19486-0024
Tel: 215-699-7733 Fax: 215-661-2605 Website: www.colorcon.com/pharma
Locations
Telephone
Facsimile
United States
Santa Ana, California
Indianapolis Indiana
Humacao, Puerto Rico
714-549-0631
317-545-6211
787-852-3815
714-549-4921
317-545-6218
787-852-0030
Europe
Dartford, Kent, England
Bougival, France
Idstein, Germany
Gallarate, Italy
Budapest, Hungary
Istanbul, Turkey
Barcelona, Spain
44-1322-293000
33-1-3082-1582
49-6126-9961-0
39-0331-776932
36-1-200-8000
90-216-465-0360
34-9-3589-3756
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49-6126-9961-11
39-0331-776831
36-1-200-8010
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34-9-3589-3792
e-mail: [email protected]
Locations
Telephone
Facsimile
Asia/Pacific
Singapore
Fuji-gun, Shizuoka, Japan
Shanghai, China
Goa, India
Seoul, Korea
65-6438-0318
81-5-4465-2711
86-21-5442-2222
91-832-288-3434
82-2-2057-2713
65-6438-0178
81-5-4465-2730
86-21-5442-2229
91-832-288-3440
82-2-2057-2179
Latin America
Buenos Aires,Argentina
Cotia, Brasil
Bogota, Colombia
Caracas, Venezuela
Santa Fe, Mexico
54-11-4552-1565
55-11-4612-4262
571-418-1202
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52-55-3000-5700
54-11-45523997
55-11-4612-3307
571-418-1257
58-212-442-8724
52-55-3000-5701&02
The information contained herein, to the best of our knowledge is true and accurate. Any recommendations or suggestions are made without warranty or
guarantee, since the conditions of use are beyond our control. Any information contained herein is intended as a recommendation for use of our products so
as not to infringe on any patent.
© Colorcon, 2005. The information contained in this document is proprietary to Colorcon and may not be used or disseminated inappropriately.
Ex_td_starch_loratadine_ver.1_aug05